Susan A. Nzenze

Epidemiology of Viral-associated Acute Lower Respiratory Tract Infection Among Children <5 Years of Age in a High HIV Prevalence Setting, South Africa, 2009–2012

Background: Data on the epidemiology of viral-associated acute lower respiratory tract infection (LRTI) from high HIV prevalence settings are limited. We aimed to describe LRTI hospitalizations among South African children aged <5 years. Methods: We prospectively enrolled hospitalized children with physician-diagnosed LRTI from 5 sites in 4 provinces from 2009 to 2012. Using polymerase chain reaction (PCR), nasopharyngeal aspirates were tested for 10 viruses and blood for pneumococcal DNA. Incidence was estimated at 1 site with available population denominators. Results: We enrolled 8723 children aged <5 years with LRTI, including 64% <12 months. The case-fatality ratio was 2% (150/8512). HIV prevalence among tested children was 12% (705/5964). The overall prevalence of respiratory viruses identified was 78% (6517/8393), including 37% rhinovirus, 26% respiratory syncytial virus (RSV), 7% influenza and 5% human metapneumovirus. Four percent (253/6612) tested positive for pneumococcus. The annual incidence of LRTI hospitalization ranged from 2530 to 3173/100,000 population and was highest in infants (8446–10532/100,000). LRTI incidence was 1.1 to 3.0-fold greater in HIV-infected than HIV-uninfected children. In multivariable analysis, compared to HIV-uninfected children, HIV-infected children were more likely to require supplemental-oxygen [odds ratio (OR): 1.3, 95% confidence interval (CI): 1.1–1.7)], be hospitalized >7 days (OR: 3.8, 95% CI: 2.8–5.0) and had a higher case-fatality ratio (OR: 4.2, 95% CI: 2.6–6.8). In multivariable analysis, HIV-infection (OR: 3.7, 95% CI: 2.2–6.1), pneumococcal coinfection (OR: 2.4, 95% CI: 1.1–5.6), mechanical ventilation (OR: 6.9, 95% CI: 2.7–17.6) and receipt of supplemental-oxygen (OR: 27.3, 95% CI: 13.2–55.9) were associated with death. Conclusions: HIV-infection was associated with an increased risk of LRTI hospitalization and death. A viral pathogen, commonly RSV, was identified in a high proportion of LRTI cases.

Temporal changes in pneumococcal colonization in a rural African community with high HIV prevalence following routine infant pneumococcal immunization.

Background: Pneumococcal conjugate vaccine (PCV) immunization of children decreases their risk of nasopharyngeal acquisition of vaccine serotypes. We studied the impact of routine infant PCV immunization alone on the epidemiology of nasopharyngeal pneumococcal colonization among a rural African community with high prevalence of HIV positivity. Methods: Two cross-sectional surveys were undertaken in a rural South African community from May to October 2009 (period 1) and 2011 (period 2). Seven-valent PCV was introduced into the public immunization program for infants in April 2009, without catch-up campaign for older children. Randomly selected households with at least 1 child <2 years of age were recruited. Nasopharyngeal swabs from all consenting household members were obtained for Streptococcus pneumoniae culture and serotyping by Quellung method. Results: The median ages (SD) of children enrolled were 4.32 (SD, 3.4) and 3.80 (SD, 3.4) years in periods 1 and 2, respectively. Overall, the prevalence of vaccine serotype colonization declined from 18.3% (368/2010) in period 1 to 11.4% (418/3659) by period 2 (P < 0.0001). This included reductions (adjusted risk ratio) of 50% [95% confidence interval (95% CI): 0.42–0.59], 34% (95% CI: 0.48–0.92) and 64% (95% CI: 0.18–0.74) in age groups <2 years, 6–12 years and adults. The prevalence of vaccine serotype colonization among primary caregivers decreased from 10.2% to 5.4% (P ⩽ 0.001) by period 2. The prevalence of nonvaccine serotype colonization increased by 35% (95% CI: 1.17–1.56) among <2-year-old children by period 2, while it declined by 45–54% among adolescents and adults. Conclusions: An indirect effect of PCV7 was realized in a high HIV prevalence setting within 2 years of PCV introduction. The unexpected decline in nonvaccine serotypes colonization among adolescents/adults may indicate lag in replacement colonization by nonvaccine serotypes in this group.

Effectiveness of pneumococcal conjugate vaccine against presumed bacterial pneumonia hospitalisation in HIV-uninfected South African children: a case–control study

Introduction We evaluated pneumococcal conjugate vaccine (PCV) effectiveness against hospitalisation for presumed bacterial pneumonia (PBP) in HIV-uninfected South African children. 7-valent PCV was introduced in April 2009 using a 2+1 schedule (doses at age 6, 14 and 39 weeks), superseded with 13-valent PCV in May 2011. Methods A matched case–control study was conducted at three public hospitals (Soweto, Cape Town and KwaZulu-Natal) between April 2009 and August 2012. PBP cases had either WHO defined radiographically confirmed pneumonia or ‘other infiltrate’ on chest radiograph with C-reactive protein ≥40 mg/L. Hospitalised controls were children admitted with a disease unlikely to be pneumococcal and matched for case age, site and HIV infection status. Age-matched community controls were enrolled from Soweto. Adjusted vaccine effectiveness (aVE) was estimated using conditional logistic regression. Results Of 1444 HIV-uninfected enrolled PBP cases, 1326 had ≥1 hospital controls (n=2075). Overall, aVE of an up-to-date PCV schedule was 20.1% (95% CI −9.3% to 41.6%) in children aged ≥8 weeks and 39.2% (95% CI 8.46% to 59.6%) among children 16–103 weeks of age. There were 889 PBP cases in Soweto with hospital controls and ≥1 community control (n=2628). The aVE using community controls was similar compared with hospital controls in Soweto, including 32.1% (95% CI 4.6% to 51.6%) and 38.4% (95% CI 7.7% to 58.8%), respectively, in age group ≥8 weeks and 52.7% (95% CI 25.7% to 69.9%) and 53.8% (95% CI 19.5% to 73.5%), respectively, in age group 16–103 weeks. Conclusions PCV implemented using a 2+1 schedule in the routine infant immunisation programme was effective at preventing PBP in HIV-uninfected children. Effectiveness estimates were similar to efficacy measured by earlier randomised controlled trials using different vaccination schedules.

Temporal changes in pneumococcal colonization in HIV-infected and HIV-uninfected mother-child pairs following transitioning from 7-valent to 13-valent pneumococcal conjugate vaccine, Soweto, South Africa

BACKGROUND We investigated the impact of infant pneumococcal conjugate vaccine (PCV) immunization on pneumococcal colonization among human immunodeficiency virus (HIV)-infected and HIV-uninfected mother-child pairs. METHODS Pneumococcal colonization was assessed in May 2010-February 2011 (period 1; 7-valent PCV era) and May 2012-April 2013 (period 2; 13-valent PCV era). Standard microbiological methods were used for pneumococcus isolation and serotyping. RESULTS In children 0-12 years, PCV13-serotype colonization decreased from period 1 to period 2 among HIV-uninfected (adjusted odds ratio [OR], 0.32; 95% confidence interval [CI], .25-.40) and HIV-infected children (adjusted OR, 0.37; 95% CI, .28-.49), while there was an increase in nonvaccine serotype colonization. Decreases in PCV13-serotype colonization were observed in HIV-uninfected women (adjusted OR, 0.44; 95% CI, .23-.81), with a similar trend in HIV-infected women. HIV-infected compared to -uninfected women had higher prevalence of overall (20.5% vs 9.7% in period 1; 13.8% vs 9.7% in period 2) and PCV13-serotype colonization (8.7% vs 5.4% in period 1; 4.8% vs 2.0% in period 2), P < .04 for all observations. CONCLUSIONS Targeted PCV vaccination of African infants in a setting with high HIV prevalence was associated with PCV13-serotype colonization reduction, including among unvaccinated HIV-infected women.

Risk Factors for Presumed Bacterial Pneumonia Among HIV-uninfected Children Hospitalized in Soweto, South Africa.

Background: Pneumonia is a leading cause of child morbidity and death. Data on risk factors can guide prevention efforts. Within a study on pneumococcal conjugate vaccine effectiveness, we investigated risk factors for presumed bacterial pneumonia (PBP). Methods: PBP cases were human immunodeficiency virus (HIV) uninfected children with lower respiratory tract infection and consolidation on chest radiograph or nonconsolidated infiltrate with C-reactive protein ≥40 mg/L hospitalized at Chris Hani Baragwanath Academic Hospital (CHBAH) in Soweto. Age-matched community controls were identified using CHBAH birth records ±1 week of case birth date. Data were analyzed using conditional logistic regression. Results: A total of 889 PBP cases (median age 9 months) were matched to 2628 controls. Crowding was a significant risk factor among well-nourished children (adjusted odds ratio [aOR]: 2.29, 95% confidence interval [CI]: 1.89–2.78), but not in those with low weight-for-age. Malnutrition was associated with PBP; strength of association was highest in the absence of crowding (aOR: 6.68, 95% CI: 4.74–9.42). Exclusive breastfeeding was protective only among HIV-unexposed children (aOR: 0.65, 95% CI: 0.54–0.78). Self-reported maternal HIV infection was a risk factor among children exclusively breastfeed up to 4 months (aOR: 2.33, 95% CI: 1.53–3.55). Having indoor tap water was protective (aOR: 0.65, 95% CI: 0.54–0.78), whereas a primary care giver who smoked was a risk factor (aOR: 5.15, 95% CI: 2.94–9.03). Conclusions: Our findings confirm several known pneumonia risk factors and highlight complex interactions between factors, including HIV exposure, breastfeeding, malnutrition and crowding. Improved housing, reduced secondhand smoke exposure and HIV prevention among women of reproductive age could lessen the child pneumonia burden.

Temporal association of infant immunisation with pneumococcal conjugate vaccine on the ecology of Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus nasopharyngeal colonisation in a rural South African community.

BACKGROUND Immunisation of children with pneumococcal conjugate vaccines (PCV) may affect the bacterial-ecology of the nasopharynx, including colonisation by Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus. The aim of this study was to evaluate the effect of infant PCV-immunisation on the nasopharyngeal ecology of these potentially pathogenic bacteria in a rural African setting. METHODS Two cross sectional surveys were undertaken from May to October in 2009 (Period-1) which coincided with the introduction of 7-valent PCV (PCV7) and in May-October 2011 (Period-2). Consenting household members, where there was a child <2 years of age in residence, had nasopharyngeal swabs undertaken for culture. RESULTS From Period-1 to Period-2 in children 0-2 years and 3-12 years, prevalence of overall S. pneumoniae colonisation decreased from 74.9% to 67.0% (p<0.001) and H. influenzae declined among children 3-12 years (55.1-45.3%, p<0.001) but not among those <2 years. The prevalence of S. aureus remained unchanged in all children. Competitive associations were found between S. pneumoniae and S. aureus and between H. influenzae and S. aureus among children. In individuals >12 years, the prevalence of colonisation decreased from 11.2% to 6.8%, 16.7% to 8.8% and 31.2% to 23.7% for S. pneumoniae, H. influenzae and S. aureus, respectively; p<0.001 for all comparions. Synergistic relationships for S. aureus with H. influenzae and S. pneumoniae were observed in both periods among this group.

Imputing the Direct and Indirect Effectiveness of Childhood Pneumococcal Conjugate Vaccine Against Invasive Pneumococcal Disease by Surveying Temporal Changes in Nasopharyngeal Pneumococcal Colonization

The limited capability in most low- to middle-income countries to study the benefit of pneumococcal conjugate vaccine (PCV) in protecting against invasive pneumococcal disease (IPD) calls for alternate strategies to assess this. We used a mathematical model to predict the direct and indirect effectiveness of PCV by analyzing serotype-specific colonization prevalence and IPD incidence prior to and following childhood PCV immunization in South Africa. We analyzed IPD incidence from 2005 to 2012 and colonization studies undertaken in human immunodeficiency virus (HIV)-uninfected and HIV-infected child-mother dyads from 2007 to 2009 (pre-PCV era), in 2010 (7-valent PCV era), and in 2012 (13-valent PCV era). We compared the model-predicted changes in IPD incidence with observed changes in IPD incidence, according to HIV status, in children aged 3 months-5 years and in women aged 18-45 years. We observed reductions in vaccine-serotype colonization and IPD due to vaccine serotypes among children and women after PCV introduction. Using the changes in vaccine-serotype colonization data, the model-predicted changes in vaccine-serotype IPD incidence rates were similar to the observed changes in PCV-unvaccinated children and adults, but not among children under age 24 months. Surveillance of colonization prior to and following PCV use can be used to impute the indirect protection afforded by PCV in unvaccinated age groups, including those in high-HIV-prevalence settings.

The potential impact of the 13-valent conjugate pneumococcal vaccine on antibiotic resistance in pneumococci

The emergence of antibiotic-resistant Streptococcus pneumoniae strains is primarily due to a selection of resistant strains by antibiotic use. The majority of antibiotic-resistant pneumococcal strains exist as a limited number of serotypes, many of which are already included in a 7-valent pneumococcal conjugate vaccine (PCV7).Additional non-PCV7 serotypes associated with antibiotic resistance include serotypes that were associated with antibiotic-resistance prior to the use of PCV7. These include an increase in nasopharyngeal colonisation and disease due to serotype 19A, both following, and in the absence of, PCV immunisation. Although transmission and disease from serotype 19A are likely to decline following immunisation with PCV13, pneumococcal disease associated with antibiotic-resistance due to serotypes not included in 13-valent PCV (PCV13) is likely to persist, albeit at lower rates. The non-PCV13 serotypes already identifed to be associated with antibiotic-resistant strains of pneumococci in the pr...

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, and identified variants in CCDC33 associated with susceptibility. Pneumococcal variation explained a large amount of invasive potential, but serotype explained only half of this variation. Newly developed methods identified pneumococcal genes involved in invasiveness including pspC and zmpD, and allowed a human-bacteria interaction analysis, finding associations between pneumococcal lineage and STK32C.

PrePex circumcision surveillance: Adverse events and analgesia for device removal

Background The PrePex medical male circumcision (MMC) device is relatively easy to place and remove with some training. PrePex has been evaluated in several countries to assess feasibility and acceptability. However, several studies have reported pain associated with removal. Objective To assess safety of PrePex and whether analgesia administered prior to removal reduces pain experienced by participants. Methods A multi-site non-randomized, prospective cohort study in which adult (18–45 years old) males requesting PrePex device male circumcision, were enrolled in six South African clinics from July 2014 to March 2015. Participants were routinely provided with analgesia shortly after the surveillance commenced following a protocol review. Analgesia regimen for device removal depended on medication availability at clinics. Results Of 1023 enrolled participants who had PrePex placed, 98% (1004) had the device removed at a study clinic. Their median age was 25 (IQR: 21–30) years. HIV sero-positivity was 3.6% (37/1023). Nurses placed and removed half of all devices. Adverse events were experienced by 2.4% (25/1023) of participants; 15 required surgical intervention: device displacement (5/14), early removals (3/14), self-removals (5/14) and insufficient skin removed (2/14). Majority (792: 79%) of participants received analgesia. Most received either paracetamol-codeine (33%), lidocaine (29%) or EMLA and Oral Combination (28%). A lower proportion of participants who received any analgesia (except for lidocaine) prior to PrePex removal experienced severe pain compared to those who received no analgesia (16.6% vs. 29%: p = 0.0001). Conclusion Reported adverse events during this PrePex active surveillance were similar to previous reports and to those of surgical circumcision. Pain medication provided prior to removal is effective at decreasing severe pain during PrePex device removal.